1-Benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride, generically known as Donepezil hydrochloride, is used for the treatment of patients with various conditions involving memory loss, such as senile dementia of Alzheimer's type (DAT). Donepezil hydrochloride is marketed as oral tablets under the trade name of Aricept®.
Eisai Co., Ltd has disclosed Donepezil and its pharmaceutically acceptable salts in U.S. Pat. No. 4,895,841.
The process for the preparation of Donepezil described in this patent, involves the reaction of 5,6-dimethoxy-1-indanone (II) with 1-benzyl-4-piperidine-1-carboxaldehyde (III) in the presence of strong base such as lithium diisopropylamide under inert atmosphere followed by reduction of the resulting compound, i.e. 1-benzyl4-[5,6-dimethoxy-1-indanon)-2-ylidinyl]methyl piperidine (IV) to give the title compound of Formula (I) with an overall yield of 27.4% (Ref. Scheme 1).

The above process involves use of lithium diisopropylamide and cryogenic temperatures. Lithium diisopropylamide is expensive, toxic, pyrophoric in nature and easily decomposes with the moisture, Further, this process is low yielding and hence economically unattractive.
Japanese patent no. JP 11-171861 discloses a process for the preparation of 1-benzyl-4-[5,6-dimethoxy-1-indanon)-2-ylidinyl]methylpiperidine (IV) by condensation of 5,6-dimethoxy-1-indanone (II) with 1-benzyl-4-formylpiperidine (III) in presence of bases such as alkali metal alkoxide in a solvent selected from tetrahydrofuran.
This process also suffers from major disadvantages such as low yield and low purity of 1-benzyl-4-[5,6-dimethoxy-1-indanon)-2-ylidinyl]methylpiperidine (IV), a key intermediate in the preparation of Donepezil hydrochloride.
The reason for such low yield has not been described in any of the prior art. We have now found that the reason for the low yield is due to the formation of an undesired hydroxy compound of Formula V.

The compound (V) is formed up to the extent of 1%, because of the compound (IV) under going oxidation during the coupling reaction. This is further carried forward as an impurity in Donepezil Hydrochloride (I). Removal of this impurity in the final stage has often proved to be difficult and requires repeated crystallizations, which finally results in the low yield of compound of Formula I.
In the instant invention, it has been found that if the reaction of 5,6-dimethoxy-1-indanone (II) with 1-benzyl-4-formylpiperidine (III) in presence of alkali metal alkoxide is carried out in presence of a catalytic amount of antioxidants such as hydroquinone, butylated hydroxytoluene (BHT) etc., results in compound (IV) with high purity and reduces the formation of compound (V) to below detectable limits and can be used as such to produce Donepezil Hydrochloride of high purity.